rs77999388

Variant names:

• chr16-20333567-C-T
• rs77999388
• NM_003361.4:c.1862-192G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003361.4(UMOD):​c.1862-192G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0171 in 152,260 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.017 (71 hom., cov: 32)
• Consequence: UMOD NM_003361.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.00
• Publications: 0 publications found

Genes affected

UMOD (HGNC:12559): (uromodulin) The protein encoded by this gene is the most abundant protein in mammalian urine under physiological conditions. Its excretion in urine follows proteolytic cleavage of the ectodomain of its glycosyl phosphatidylinosital-anchored counterpart that is situated on the luminal cell surface of the loop of Henle. This protein may act as a constitutive inhibitor of calcium crystallization in renal fluids. Excretion of this protein in urine may provide defense against urinary tract infections caused by uropathogenic bacteria. Defects in this gene are associated with the renal disorders medullary cystic kidney disease-2 (MCKD2), glomerulocystic kidney disease with hyperuricemia and isosthenuria (GCKDHI), and familial juvenile hyperuricemic nephropathy (FJHN). Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2013]

UMOD Gene-Disease associations (from GenCC):

• autosomal dominant medullary cystic kidney disease with or without hyperuricemia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• glomerulocystic kidney disease with hyperuricemia and isosthenuria

  Inheritance: AD Classification: DEFINITIVE Submitted by: Laboratory for Molecular Medicine
• familial juvenile hyperuricemic nephropathy type 1

  Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal dominant medullary cystic kidney disease with hyperuricemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 16-20333567-C-T is Benign according to our data. Variant chr16-20333567-C-T is described in ClinVar as Benign. ClinVar VariationId is 1261623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003361.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMOD	NM_003361.4	MANE Select	c.1862-192G>A		intron	N/A	NP_003352.2	P07911-1
	UMOD	NM_001378234.1		c.2003-192G>A		intron	N/A	NP_001365163.1
	UMOD	NM_001378235.1		c.2003-192G>A		intron	N/A	NP_001365164.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMOD	ENST00000396138.9	TSL:5 MANE Select	c.1862-192G>A		intron	N/A	ENSP00000379442.5	P07911-1
	UMOD	ENST00000396134.6	TSL:2	c.1961-192G>A		intron	N/A	ENSP00000379438.2	P07911-5
	UMOD	ENST00000863077.1		c.2024-192G>A		intron	N/A	ENSP00000533136.1

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2591 AN: 152142 Hom.: 71 Cov.: 32

Gnomad AFR AF: 0.0592

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00688

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00812

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0171 AC: 2602 AN: 152260 Hom.: 71 Cov.: 32 AF XY: 0.0164 AC XY: 1223 AN XY: 74468

African (AFR) AF: 0.0593 AC: 2462 AN: 41550

American (AMR) AF: 0.00687 AC: 105 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67996

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.0204 Hom.: 10

Bravo AF: 0.0195

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.35
DANN	Benign	0.62
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs77999388; hg19: chr16-20344889;